Repeated exposure to drugs of abuse leads to long lasting changes in reward- and stress-related neuronal circuitry. Important components of this circuitry include the caudate-putamen, nucleus accumbens, central nucleus of the amygdala, and the ventral tegmental area (VTA). Several studies have suggested a role for molecular components of the circadian clock as key players in drug reward and drug-associated responses. McClung et al. (2005) identified a key role for the circadian locomotor output cycles kaput (CLOCK) gene in the regulation of drug reward. Mice bearing a dominant negative mutation in the CLOCK gene (CLOCK 19 mice) exhibit increased cocaine sensitivity and preference. Furthermore, these mice exhibit increased locomotor activity, reduced anxiety-like and depression-like behavior, increased intracranial self-stimulation (ICSS) at a lower threshold, and increased dopaminergic cell activity in the VTA (McClung et al., 2005;Roybal et al., 2007). The goal of the proposed research training plan is to identify the role of CLOCK in specific brain regions as a mediator of ethanol-related behavior. First, we will determine how chronic binge ethanol consumption regulates expression levels of CLOCK in reward- and stress-related regions of the brain using in situ hybridization. Second, we will determine how a dominant negative mutation of CLOCK (CLOCK 19 mice) affects measures of operant oral ethanol self-administration. Finally, we will determine if CLOCK function in the VTA is important in modulating ethanol intake and relapse-like drinking behavior using RNAi. Further examination of the role of circadian genes in alcohol-related behaviors will have exciting translational significance for treatment, as many recovering addicts exhibit circadian disruptions that persist in recovery and contribute to relapse. I have a strong interest to perform alcohol research at the molecular and behavioral levels. The goal of this training plan is to provide me with detailed expertise in the use of cutting edge techniques and approaches, conversion of data into high-visibility publications, and prepare me for a transition to independence. I am motivated, diligent, and dedicated to advancing the treatment of alcoholism. This plan, combined with the excellent group of researchers at UTSW will allow me to obtain my goals outlined in this proposal, as well as prepare me for a successful independent research career in the alcohol and drug abuse field. The funding of this NRSA application is instrumental in my success. PUBLIC HEALTH RELEVANCE: The proposed work will provide insights into the role of circadian genes in alcohol consumption and withdrawal from chronic binge-drinking, which may contribute to increased drug craving and relapse. Application of this knowledge may provide insights into new treatment strategies during drug withdrawal thereby decreasing the relapse rate and improving treatment outcomes.